Opiate compounds are potent and effective centrally acting analgesic agents, but systemic administration is usually accompanied by undesirable effects such as sedation, gastrointestinal disturbance, and respiratory depression. In addition, tolerance, withdrawal, and addiction inevitably result from prolonged use. This proposal concerns the function of opioid receptors in the periphery, and how their activation contributes to an endogenous opioid analgesia system operating outside the central nervous system. We have shown in normal cornea and skin that direct peripheral application of morphine is not effective in altering acute nociceptive responses. However, in inflamed tissue, peripheral morphine reverses behavioral hyperalgesia in cornea and reduces excitability of identified cutaneous nociceptors in a concentration-dependent and naloxone reversible fashion. We now seek to determine under what conditions this endogenous opioid system is effective, and what mechanisms contribute to enhanced availability of peripheral opioid receptors after injury or inflammation. Electrophysiological techniques will be used to determine (1) which opioid receptor types mediate the inhibitory effects of morphine on identified afferent neurons innervating inflamed somatic tissue, and (2) if sensory neurons develop a sensitivity to morphine in an experimental model of neuropathic pain. Quantitative immunohistochemistry will determine (3) the time course of changes in expression of opioid receptors in the somata and peripheral processes of sensory neurons under inflammatory and neuropathic conditions, and (4) if increased numbers of opioid receptors are detectable on the membranes of peripheral processes of sensory neurons following inflammation. Better understanding of how endogenous opioid systems are regulated would provide valuable insights into potential development of therapeutic alternatives to traditional systemic delivery of opiates for the relief of pain.